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Erlotinib, and preparation method of new intermediate of erlotinib

A kind of technology of erlotinib and intermediate, applied in the field of drug development

Inactive Publication Date: 2013-10-23
SHANGHAI BOLI BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, these routes have the following defects: 1) the consumption of chlorinated reagent is large, the corrosion of reaction equipment is obvious, and chlorinated product intermediate 7 is unstable: See the literature (Organic Process Research&Development 2007, vol.11, 813-816; Synthetic Communications 2007, vol.37, 3409-3415); 2) The content of a single impurity is relatively high: as mentioned in many literatures, the Elo The largest single impurity in the final product of tinib is the derivative of N-methoxyethyl 10:
But the starting material of this route is relatively expensive, and the cost is relatively high

Method used

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  • Erlotinib, and preparation method of new intermediate of erlotinib
  • Erlotinib, and preparation method of new intermediate of erlotinib
  • Erlotinib, and preparation method of new intermediate of erlotinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1 3, the preparation of 4-bis-(2-methoxyethoxy)-benzoic acid (2-methoxyethyl ester)

[0055] In a 1L reaction flask, add 20g of 3,4-dihydroxybenzoic acid and 400mL of acetone, then add 30g of potassium carbonate, 1g of potassium iodide, and 30mL of 2-bromoethoxymethyl ether, heat to reflux for 12 hours, cool and filter, and the filtrate After concentration, 38.8 g of a light yellow solid was obtained, with a yield of 91.5%.

[0056] 1 H NMR (CDCl 3 , 400MHz) δ7.72(dd, J=8.4, 2.0Hz, 1H), 7.61(d, J=2.0Hz, 1H), 6.93(d, J=8.4Hz, 1H), 4.47-4.44(m, 2H ), 4.23-4.20(m, 4H), 3.83-3.80(m, 4H), 3.74-3.72(m, 2H), 3.47(s, 6H), 3.44(s, 3H).

[0057] ESI-MS m / z 328.6M + .

Embodiment 2

[0058] Example 2 Preparation of 2-nitro-4,5-bis-(2-methoxyethoxy)-benzoic acid (2-methoxyethyl ester)

[0059] In a 1L reaction flask, add 3,4-bis-(2-methoxyethoxy)-benzoic acid (2-methoxyethyl ester) 38.5g and 120mL acetic acid, keep the temperature below 5°C and add 45% HNO3 (20mL) was reacted for 30 minutes, then 70% H2SO4 (40mL) was added dropwise, and the solution was reacted at room temperature for 2 hours. Add ice water and 50% NaOH to make it alkaline, extract with ethyl acetate, filter, and concentrate the filtrate to obtain 32.0 g of a light yellow solid with a yield of 89%.

[0060] 1 H NMR (CDCl 3 , 400MHz) δ7.54(s, 1H), 7.14(s, 1H), 4.47(t, J=5.2Hz, 1H), 4.26-4.24(m, 4H), 3.82-3.79(m, 4H), 3.71 (t, J=5.2Hz, 2H), 3.46(s, 6H), 3.40(s, 3H).

[0061] ESI-MS m / z 373.6M + .

Embodiment 3

[0062] Example 3 Preparation of 2-amino-4,5-bis-(2-methoxyethoxy)-benzoic acid (2-methoxyethyl ester)

[0063] In a 500mL reaction flask, add 2-nitro-4,5-bis-(2-methoxyethoxy)-benzoic acid (2-methoxyethyl ester) 15g and 150mL methanol, add 10% Pd / C, hydrogenation under normal pressure for 6 hours, filtered, and the filtrate was concentrated to obtain 14.3 g of a brown solid, with a yield of 99%.

[0064] ESI-MS m / z 343.6M + .

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Abstract

The invention discloses an erlotinib intermediate compound. The erlotinib intermediate compound is characterized by having a structural general formula (I); in the formula (I), R1 is selected from H, NO2, CN, halogen atom, COOH, CF3 and SO2CF3; the halogen atom is selected from F and Cl. The erlotinib prepared by the intermediate has the advantages of cheap and readily available raw materials, low impurity content, basically no checkout and the like.

Description

technical field [0001] The invention belongs to the technical field of drug development, and in particular relates to a preparation method of erlotinib and a new intermediate thereof. Background technique [0002] Erlotinib hydrochloride tablets, whose trade name is Tarceva, was developed by Roche Pharmaceuticals for the treatment of locally advanced or metastatic non-small It can also be used in combination with gemcitabine as a first-line treatment for locally advanced, resectable or metastatic pancreatic cancer. It is an epidermal growth factor receptor (Epidermal Growth Factor Receptor, EGFR) tyrosine kinase inhibitor. Structurally, erlotinib belongs to quinazoline compounds, and its chemical name is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinoline amine. Its structural formula is as follows: [0003] [0004] The preparation method of erlotinib was first seen in WO96 / 30347, which is the synthetic route mentioned in the compound patent developed by Pfizer ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04C07D239/94
Inventor 李本陈力
Owner SHANGHAI BOLI BIO TECH
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